A PBPK-VBE approach for bioequivalence extrapolation of senaparib capsule strengths in the context of nonlinear pharmacokinetics: bridging from the clinical starting dose to the linear pharmacokinetic range.

AIMS: Senaparib (Sepalna®), a novel oral poly (adenosine diphosphate -ribose) polymerase (PARP) 1/2 inhibitor, was approved in China in 2025 as maintenance therapy for advanced ovarian cancer. The recommended starting dose is 100 mg once daily, which may be adjusted to 80 mg, 60 mg, or 40 mg to manage adverse events. While conventional bioequivalence (BE) clinical studies established equivalence between the 10 mg and 20 mg capsules strengths at the 100 mg dose level, these findings cannot be extrapolated to the lower dose range due to senaparib's nonlinear pharmacokinetics and the current absence of definitive regulatory guidance for such scenarios. This study aimed to evaluate the bioequivalence between the 10 mg and 20 mg capsule strengths of senaparib, a drug exhibiting nonlinear pharmacokinetics, across the 20-80 mg dose range. METHODS: We developed and validated an integrated approach combining physiologically based pharmacokinetic (PBPK) modeling with in vitro dissolution data to evaluate virtual bioequivalence (VBE) between the two capsule strengths across the 20-80 mg dose range. RESULTS: Under all evaluated conditions including variations in sample size, intra-individual variability levels, and prandial states (fasted and fed), the geometric mean ratios (GMRs) of key pharmacokinetic (PK) parameters consistently approached 100%, thereby confirming bioequivalence across the specified dosing range. CONCLUSION: This PBPK-VBE framework provides supportive evidence for bioequivalence bridging of senaparib capsule strengths across the linear dose range, illustrating the potential utility of this approach for formulation bridging when direct clinical BE studies across all dose levels are impractical.